Breast cancer remains one of the most significant health threats to women today. The American Cancer Society estimated that in the United States there were 176,300 cases and 43,700 deaths due to breast cancer in 1999. The major cause of mortality in breast cancer patients is tumor metastases, but only a minority of patients exhibit clinically detectable metastases at diagnosis. The long-term risk of tumor recurrence is well recognized: metastases may appear even 10 to 20 years after curative primary tumor removal. Clinical studies of tumor metastasis in breast cancer patients show that tumor cells can undergo a period of dormancy followed by rapid growth during relapse. Thus, a dormant tumor population remains clinically undetectable for months or years and consequently poses a continuous risk of recurrence. The molecular mechanisms controlling tumor dormancy remain unknown. However, our laboratory has recently established that human breast cancer micrometastases have decreased rates of proliferation and angiogenesis, with no difference in apoptosis, when compared to lymph node macrometastases. Based on these findings we hypothesize that there are differences in gene expression between micro- and macrometastases that account for the phenotypic differences in angiogenesis and proliferation. Therefore activation of genes that increase tumor cell growth and angiogenesis directly or indirectly (loss of suppressor genes) are necessary for the growth of dormant micrometastases. By comparing genetic differences between micrometastases and macrometastases, we may be able to discover new genes or novel gene expression patterns that are responsible for tumor angiogenesis and proliferation that occur in the target metastatic organ. The specific aims of our proposal are: 1) to characterize defined genes in micrometastases versus macrometastases, 2) gene discovery in endothelial cells and micrometastases, 3) molecular characterization of candidate genes. By comparing genetic differences between micro- and macrometastases, we may discover novel genes that are responsible for tumor angiogenesis and proliferation that occur in the target metastatic organ. These genes could be pharmacogenomic targets for future treatment strategies.